This project is focused on the development, conduct and analysis of patient-oriented studies in people with HIV and cancer as well as select viral associated cancers that are most common in people with HIV. Major activities have included the development of 3 new treatment protocols: 1. EVALUATION OF ANTI-PD1 THERAPY IN PATIENTS WITH HIV AND CANCER. Patients with HIV are at an increased risk of viral associated malignancies and smoking related cancers (i.e. lung cancer) that may be responsive to checkpoint inhibition using monoclonal anti-bodies against PD-1. Furthermore, the HIV reservoir may be altered by anti-PD-1 therapy. However, the safety of anti-PD-1 therapy in patients with HIV has not been established. CITN12: Pembrolizumab in Treating Patients with HIV and Relapsed, Refractory or Disseminated Neoplasms (NCT02595866; open to accrual) is a phase 1 study of pembrolizumab, an anti-PD-1 monoclonal antibody, which will be evaluated in 3 cohorts of HIV-infected patients on effective antiretroviral therapy, stratified by CD4+ T-cell count (100-200, 200-350, 350). In addition to evaluating safety and anti-tumor effect, the study will evaluate HIV latency reversal, evaluation intermediated biomarkers of the HIV reservoir, and evaluate the effect of PD-1 therapy on mucosa shedding of oncogenic viruses (EBV, KSHV, and HPV). These correlative objective will inform HIV Cure research. 2. TREATMENT OF PRIMARY EFFUSION LYMPHOMA and KAPOSI SARCOMA WITH IMiD-DRUG BASED REGIMENS. Pomalidomide is a 3rd generation immune modulatory derivative of thalidomide drug (IMiD) that lead to objective responses in a 16/22 (73%) in a phase I/II study performed in the HAMB. Additionally, IMID drugs may be particularly useful in the treatment of primary effusion lymphoma through downregulation of IRF4 and prevention of downregulation of MHC1 by KSHV. The primary objectives of these studies are to a) evaluate the safety and efficacy of pomalidomide in combination with liposomal doxorubicin in patients with advanced KS, including KS with concurrent KICS or KSHV-MCD (Pomalidomide in Combination with Liposomal Doxorubicin in People with Advanced or Refractory Kaposi Sarcoma, NCT02659930; open to accrual) and b) evaluate the safety and efficacy of lenalidomide combined with rituximab and dose adjusted EPOCH (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone) in primary effusion lymphoma (Phase I/II Study of Lenalidomide Combined with Modified DA-EPOCH and Rituximab [EPOCH-R2] in Primary Effusion Lymphoma or KSHV-associated Large Cell Lymphoma, NCT02911142, open to accrual). Secondary objectives include evaluation of the effects of these regimens on immune parameters as measured by flow cytometry and circulating immune factors. 3. TREATMENT OF AIDS-RELATED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIATION SPARING THERAPY. Patients with AIDS remain at an elevated risk of AIDS-related primary central nervous system lymphoma (PCNSL), which is an EBV associated tumor. PCNSL continues to make up 10% of all lymphomas in people with HIV, and it disproportionately effects young people with PCNSL. There is no defined therapy, and the use of whole brain radiation may be associated with severe neurotoxicity. The primary objective is to evaluate overall survival in in patients with AIDS-related PCNSL treated with antiretroviral therapy combined with the anti-CD20 monoclonal antibody, rituximab, and high dose methotrexate. Secondarily, we will evaluate long term neurocognitive outcomes in this patient population. (NCT00267865, open to accrual) 4. NATURAL HISTORY OF KSHV-ASSOCIATED DISEASES. Patients with HIV and KSHV co-infection are at increased risk of life threatening IL-6 associated inflammatory manifestations that can be categorized as KSHV-associated multicentric Castleman disease (KSHV-MCD) OR KSHV-associated inflammatory cytokine syndrome (KICS). The primary objective is to evaluate the role of KSHV-associated immune dysregulationin the pathogenesis, clinical presentation, and prognosis of primary effusion lymphoma and advanced KS. Secondary objectives include evaluation of incorporation of biomarkers (KSHV-viral load, flow cytometry, immunoglobulin gene rearrangement) for disease categorization and risk stratification. Accrual and data analysis is ongoing for natural history studies evaluating KSHV-MCD (NCT00092222) and KICS (NCT01419561). An evaluation of biomarkers within a completed study of antiretroviral therapy versus antiretroviral therapy combined with chemotherapy in South Africa (NCT00380770) has been developed in collaboration with South African investigators.